NAS research utilizes a rat model of cognitive aging validated over the course of many earlier studies. This model has enabled productive collaborations with intramural investigators and extramural laboratories at a number of institutions including Johns Hopkins University, UC Irvine, the Mount Sinai School of Medicine, and University of Washington. Important features of the model are that genetically outbred, Long-Evans rats are tested using a sparse training protocol in a version of the Morris water maze optimally tuned to interrogate the functional integrity of the hippocampus. This protocol reveals prominent and reliable individual differences in spatial learning and memory at 24+ months of age, with impairment qualitatively similar to the effects of hippocampal damage in young subjects. Subjects with sensorimotor deficits that might be misinterpreted as cognitive in origin are excluded, and spatial learning capacities among the remaining aged rats are continuously distributed across a broad range, with some performing on par with normal young adults, and others that display significant impairment. In this way the model enables comparisons across subjects matched according to chronological age but distinguished by differences in the status of hippocampal memory. Previous studies confirm that behavioral outcomes in this setting provide a valuable framework for exploring the neurobiology of cognitive aging, and for developing potential therapeutic interventions. Significant progress during the reporting period has been realized on several fronts. Growing interest in the emerging field of cognitive neuroepigenetics has centered on the therapeutic potential of histone deacetylase inhibitor (HDACi) administration. How experience interacts with histone acetylation levels to modulate gene and protein expression, however, is not well understood. In recently published studies targeting this issue, we tested whether brief behavioral training in a learning task modulates the hippocampal gene expression response to acute systemic HDACi administration (Sewal et al., 2015). Cognitive training powerfully modulated the response to HDACi treatment, increasing the number of genes regulated nearly 10-fold over drug alone, including many not typically linked to neural plasticity. The effect of behavioral training alone was also substantial, but the specific genes and gene networks affected were largely non-overlapping with the influence of the same experience provided together with HDACi administration. Thus, the influence of ongoing experience qualitatively shifts the gene expression response to elevated histone acetylation, yielding a unique synergistic interaction, not simply the enhancement of the transcriptome usually engaged by recent experience. A follow-up experiment tested whether the synaptic protein response to HDACi administration is similarly dependent on recent cognitive experience, and whether this plasticity is disrupted in aged rats with memory impairment. Extending the results for gene expression, synaptic protein levels were only elevated in the young adult hippocampus when HDACi administration was provided in conjunction with behavioral training. In contrast, combined treatment had no effect on synaptic protein levels in the aged hippocampus. The significant implications for the development of therapeutic strategies targeting epigenetic control is that the response to treatment may vary markedly in relation to an individual's unique history and ongoing behavior, and that the capacity for regulation is blunted in aging. Another recently published study extended our approach to ask whether cognitive aging arises from network-level dysfunction involving the interactions between multiple memory systems (Tomas Pereira et al., 2015). With this aim in mind we developed a behavioral testing procedure that required rats to learn competing hippocampal and striatum-dependent place and response strategies in succession. As predicted on the basis of earlier work, young adult rats acquired place strategies more rapidly than response, whereas aged rats with impaired spatial memory displayed the opposite pattern. The striking new finding, however, was that aged rats with intact spatial memory displayed a qualitatively different pattern of performance in which place and response strategies were learned equally rapidly, without the significant disruption observed in both young and aged-impaired subjects when they switched between the two task strategies. These findings suggest that successful cognitive aging reflects a qualitatively distinct process of neuroadaptation, not simply a slower rate of aging and endurance of youthful cognitive processing. We tested this view in a final task manipulation that, for the first time, required animals to switch between response and place strategies within a single test session, increasing demands on cognitive flexibility, and engaging capacities thought to require the prefrontal cortex. Animals were euthanized shortly after training, and in situ hybridization for the plasticity-related immediate-early gene Arc provided a window on the neural networks activated during testing. A major finding of interest in the present context is that, among the multiple brain regions examined, activation patterns involving the pre- and infralimbic divisions of the prefrontal cortex uniquely distinguished aged rats with preserved spatial memory and superior switching ability. These results extend other recent studies from our group examining the contribution of Arc transcription, translation and decay to impaired plasticity in aging (Fletcher et al., 2014), and they are among the first to provide clues about the potential circuit substrates of cognitive reserve and adaptation. Ongoing efforts also focus on a network level of analysis, examining potential disruption in the large-scale organization and interaction between anatomically or neurochemically defined circuits. In collaboration with investigators in the Neuroimaging Research Branch at NIDA, for example, we are using in vivo brain imaging methods in our established rat model to document the status of network functional connectivity in relation to individual differences in the cognitive outcome of aging. Results currently in preparation for publication demonstrate that functional connectivity among regions comprising the default mode network is selectively reduced among aged rats that display spatial memory important. Unlike human research, where the contribution of prodromal neurodegenerative disease can be difficult to determine with confidence, these findings suggest that altered network activity may be among the earlier signatures comprising the unique neurobiological setting that confers cognitive aging as a key risk for Alzheimers disease. In future studies taking advantage of this preclinical animal model we hope to test whether non-invasive brain stimulation aimed at normalizing cortical network activity rescues cognitive impairment and reverses associated neurochemical abnormalities. Ultimately, the use of in vivo brain imaging and non-invasive brain stimulation approaches that are already approved for other conditions should facilitate the rapid clinical translation of encouraging results.